A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Natalizumab therapy for moderate to severe Crohn disease in adolescents.

OBJECTIVES: This study evaluated the safety, tolerability, and efficacy of natalizumab, a humanized monoclonal immunoglobulin-G4 antibody to [alpha]4 integrin, in adolescent patients with moderately to severely active Crohn disease (CD). PATIENTS AND METHODS: In a single-arm study, 38 adolescent patients (ages 12-17 y) with active CD (Pediatric Crohn Disease Activity Index [PCDAI] >30) received 3 intravenous infusions of natalizumab (3 mg/kg) at 0, 4 and 8 weeks. The primary analysis was safety, assessed by adverse events, laboratory results, and vital signs. Pharmacokinetic and pharmacodynamic measurements and formation of anti-natalizumab antibodies also were analyzed. Efficacy outcomes were assessed by changes in PCDAI, quality of life (IMPACT III), and levels of C-reactive protein and serum albumin. RESULTS: Thirty-one patients (82%) received 3 natalizumab infusions. The most common adverse events were headache (26%), pyrexia (21%) and CD exacerbation (24%). Clinical response (> or =15-point decrease from baseline PCDAI) and remission (PCDAI < or =10) rates were greatest at week 10 (55% and 29%, respectively). Three patients (8%) tested positive for anti-natalizumab antibodies. The peak level (61.0 and 66.3 microg/mL) and half-life (92.3 and 96.3 h) of natalizumab were comparable after the first and third infusions. Mean [alpha]4 integrin receptor saturation was 93% at 2 hours and <40% at 4 weeks after the first and third infusions. Increase from baseline in circulating lymphocytes ranged from 106% to 122% at 2 weeks and 45% to 65% at 4 weeks after each infusion. CONCLUSION: Natalizumab (3 mg/kg) was well tolerated in these adolescent patients with active CD, with a safety and efficacy profile similar to that of adult natalizumab-treated CD patients. Future studies should evaluate long-term safety and efficacy.